The 2021 Adult and Pediatric Anticoagulation Guidelines for patients on extracorporeal membrane oxygenation (ECMO) recommend a target partial thromboplastin time (PTT) between 60 and 85 seconds when unfractionated heparin (UFH) is administered as an anticoagulant. However, institutions may develop their own protocols in the absence of solid evidence regarding patient anticoagulation during ECMO support. We aimed to determine the association between maintenance anticoagulation with different PTT ranges among patients receiving UFH or no anticoagulation therapy and the occurrence of hemorrhagic complications in adults receiving ECMO support. We conducted a prospective cohort study that included 277 adults on ECMO support. Kaplan–Meier curves were used to compare the time-dependent risk of hemorrhagic events. The association was estimated using the hazard ratio, and the risk was estimated using the multivariate Cox proportional hazards model adjusted for covariates. The time-dependent risk of hemorrhagic events during ECMO support was 2.97-fold higher in patients with a PTT greater than 70 than in patients under no UFH therapy (95% confidence interval [CI]: 1.53–5.77; p = 0.001). An association was observed between target PTT and hemorrhagic complications, with the risk of hemorrhagic complications being higher when maintaining PTT values greater than 70 seconds during ECMO support.